Use of protein kinase C inhibitors to enhance the clinical efficacy of oncolytic agents and radiation therapy

Abstract

A method for treating neoplasms is disclosed, particularly using the beta-isozyme selective PKC inhibitor, (S)-3,4-[N, N'-1,1'-((2''-ethoxy)-3'''(O)-4'''-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione or one of its salts, such PKC inhibitors enhance the clinical efficacy of oncolytic agents and radiation therapy.

What is claimed is:  
     
       1. A method for treating a neoplastic condition sensitive to the combination below which comprises administering to a mammal in need of such treatment an effective amount of an oncolytic agent having an anti-neoplastic effect in combination with a protein kinase C inhibitor selective for a beta-1- or beta-2- isozyme of protein kinase C, wherein the protein kinase C inhibitor is administered in an amount sufficient to enhance the anti-neoplastic effect of the oncolytic agent, and wherein the protein kinase C inhibitor is a bis-indolylmalemide and has the following formula:                    
       wherein:                    
       R 1  is  
       R 1′  is hydrogen, C 1 -C 4  alkyl, aminoalkyl, monoalkylaminoalkyl, or dialkylaminoalkyl;  
       R 2  and R 2′  are independently hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, C 1 -C 3  alkylthio, S(O)C 1 -C 3  alkyl, or CF 3 ;  
       R 3  is hydrogen or CH 3 CO-;  
       R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , R 7  and R 7′ are independently hydrogen, halogen, alkyl, hydroxy, alkoxy, —COO(C 1 -C 3  alkyl), CF 3 , nitro, amino, acetylamino, monoalkylamino, dialkylamino, alkylthio, C 1 -C 3  alkylthio, or S(O)C 1 -C 3  alkyl;  
       R 12  is hydrogen, alkyl, haloalkyl, cycloalkyl,acetyl, aryl, —CH(aryl) 2 , amino, monoalkylamino, dialkylamino, guaidino, —C(=N(alkoxycarbonyl))NH(alkyoxycarbonyl), amidino, hydroxy, carboxy, alkoxycarbonyl or heterocyclyl;  
       p and q are independently 1, 2, 3, or 4;  
       s is 0, 1, 2 or 3;  
       t is 1 or 2;  
       u is 0 or 1; or a pharmaceutically acceptable salt or solvate thereof.